What Is Pralsetinib (Gavreto)? FDA Approval, Licensing and Reimbursement in Türkiye

• FDA Approval: Yes. First Approval Date: September 4, 2020 (accelerated approval)
• Brand Name: Gavreto
• Active Ingredient: Pralsetinib
• Route of Administration: Oral capsules
• Class: Tyrosine kinase inhibitor (RET inhibitor)
• Category: Targeted antineoplastic agent
• Manufacturers: Blueprint Medicines Corporation and Genentech Inc.
• Distribution in Türkiye: Gavreto is not licensed in Türkiye. It is not on the Turkish Medicines and Medical Devices Agency (TİTCK) overseas medicines list. Procurement from abroad through special authorization may be possible.
• Approved Cancers: Metastatic RET fusion-positive non-small cell lung cancer, RET-mutated medullary thyroid cancer, and RET fusion-positive differentiated thyroid cancer resistant to radioactive iodine.

What Is Pralsetinib and How Does It Work?

Pralsetinib is an oral tyrosine kinase inhibitor (TKI) providing targeted treatment for genetically defined cancers. It is used particularly in tumors with fusions or activating mutations in the RET (Rearranged during Transfection) proto-oncogene. RET normally participates in signaling that regulates growth and differentiation, but activation by mutation or fusion can trigger uncontrolled proliferation and tumor development.

How Does It Work?

• Recognition of a RET Fusion or Mutation: RET alterations cause cell-surface receptors to remain continuously active, stimulating intracellular pathways, particularly RAS/MAPK and PI3K/AKT, and driving uncontrolled tumor-cell proliferation.
• Inhibition of Kinase Activity: Pralsetinib competitively binds to the ATP-binding site, blocking RET kinase phosphorylation. This effect occurs in cancers including RET fusion-positive non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).
• Interruption of Signaling: RET-activated downstream pathways, including MAPK, JAK/STAT, and PI3K/AKT, are suppressed, arresting the tumor-cell cycle. Apoptosis (programmed cell death) is triggered, and angiogenesis and invasion decrease.

FDA (US Food and Drug Administration) Approval History

• June 3, 2019: Updated ARROW findings presented at ASCO 2019 showed durable tumor shrinkage with Blueprint Medicines' highly selective RET inhibitor BLU-667 in patients with RET alterations.
• January 8, 2020: Blueprint Medicines announced topline pralsetinib findings in RET fusion-positive non-small cell lung cancer and began a rolling new drug application to the FDA.
• July 1, 2020: Blueprint Medicines announced submission of a new drug application to the FDA for pralsetinib in advanced RET-mutated and RET fusion-positive thyroid cancers.
• September 4, 2020: The FDA approved Gavreto (pralsetinib) for metastatic RET fusion-positive non-small cell lung cancer.
• December 1, 2020: Genentech announced FDA approval of Gavreto for advanced or metastatic RET-mutated and RET fusion-positive thyroid cancers.
• August 9, 2023: The FDA granted Gavreto full (regular) approval for non-small cell lung cancer with RET gene fusions.

Licensing in Türkiye

It has not yet been officially licensed in Türkiye. It may be obtained from abroad through Ministry of Health special authorization procedures. It is not on the TİCK overseas medicines list.

Mechanisms of Resistance

• Secondary Mutations Within RET: Pralsetinib inhibits the RET kinase domain. Tumor cells may develop secondary mutations in this region that prevent binding. RET G810C/S/R mutations are the most common resistance mutations. These structurally change the drug-binding pocket and reduce pralsetinib's effect. This is “on-target” resistance originating in the target gene itself.
• Activation of Bypass Pathways: When RET is blocked, tumor cells may continue growing through alternative pathways, including MET amplification, KRAS, NRAS, or BRAF mutations, and EGFR or FGFR activation. These sustain growth and survival through kinases other than RET.
• Pharmacokinetic/Pharmacodynamic Changes: Increased drug efflux (through P-gp expression). Accelerated metabolism. Changes in tumor-microenvironment factors such as pH or oxygen levels may alter drug bioavailability.
• Histologic Transformation or Tumor Heterogeneity: The tumor may change cell type and acquire a different phenotype, such as small cell transformation. Different clones may emerge in the same patient, some losing RET dependence and becoming treatment-resistant.
• Loss or Reduction of the Drug Target: Reduced or lost RET expression removes the target to which the drug binds. The cell may then maintain proliferation through other pathways.

Absorption

• Oral capsules
• High bioavailability; maximum plasma concentration (Cmax) is reached approximately 2 hours after a single dose.
• A high-fat meal does not significantly affect systemic drug levels, so it may be taken with or without food.
• Absorption is not sensitive to gastric pH.

Distribution

• Volume of distribution (Vd): approximately 500 L, indicating good tissue penetration.
• Plasma protein binding: 97%
• Particularly high binding to albumin.
• The free (active) drug fraction is low, but tissue activity is strong.

Metabolism

• Pralsetinib is metabolized mainly in the liver.
• Main enzyme: CYP3A4. CYP3A4 inhibitors such as ketoconazole may therefore increase blood drug levels.
• CYP3A4 inducers such as rifampin may reduce efficacy.
• Minor metabolism also occurs through CYP2D6 and CYP1A2.

Elimination

• Half-life (t1/2): approximately 22 hours
• Suitable for 1 daily dose.
• Total clearance: ~15 L/hour
• Feces: 73% (main route)
• Urine: 6%
• Most metabolites are inactive and eliminated through the liver.

Dose Range

• 400 mg orally 1 time daily.
• May be taken with or without food.
• Do not chew, crush, or split the capsules; swallow them whole.

Drug Interactions

• Pralsetinib is a tyrosine kinase inhibitor metabolized primarily by hepatic CYP3A4. Caution is therefore needed with drugs affecting CYP3A4.
• CYP3A4 inhibitors, such as ketoconazole, clarithromycin, or ritonavir, can increase pralsetinib blood levels and toxicity risk. Dose reduction may be necessary; the generally recommended reduction is from 400 mg/day to 200 mg/day.
• Conversely, CYP3A4 inducers, including rifampin, carbamazepine, phenytoin, or herbal products such as St. John's wort, can accelerate metabolism and reduce efficacy. These drugs should be avoided where possible.
• Pralsetinib is also a substrate of P-glycoprotein (P-gp) and BCRP (Breast Cancer Resistance Protein). Drugs inhibiting these transporters may increase absorption and bioavailability, potentially causing toxicity. Transporter-inducing drugs may reduce absorption and efficacy.
• No clinically significant interaction has been reported with acid-suppressing drugs such as proton pump inhibitors or H2 receptor antagonists. Because pralsetinib absorption is not dependent on gastric pH, it may be used safely with them.
• Pralsetinib may also rarely prolong QT. Caution is needed with QT-prolonging drugs, such as amiodarone, moxifloxacin, or methadone, and ECG monitoring may be necessary. Electrolyte imbalances such as hypokalemia and hypomagnesemia should also be corrected.
• Drug interactions require careful assessment during pralsetinib treatment. Dose adjustment, clinical monitoring, and alternative drugs when necessary are important.

Points Requiring Attention

• Hypertension (High Blood Pressure): Pralsetinib may raise blood pressure by affecting vascular smooth muscle cells. Monitor blood pressure regularly and stabilize uncontrolled hypertension before treatment. Start antihypertensive treatment or adjust existing therapy when necessary.
• Interstitial Lung Disease / Drug-Related Pneumonia: A rare but serious complication. Stop treatment and perform a pulmonary assessment if dry cough, shortness of breath, or fever develops. Systemic corticosteroids may be needed.
• Hepatotoxicity (Liver Toxicity): Pralsetinib may increase liver enzymes. AST, ALT, and bilirubin should be monitored regularly during treatment. Severe increases in liver function tests may require dose reduction or temporary interruption.
• Hematologic Toxicities: Anemia, neutropenia, and thrombocytopenia may occur. Monitor a complete blood count (CBC) at baseline and regularly afterward. Dose adjustment is needed for moderate to severe cytopenias.
• QT Prolongation: Rare QTc prolongation may occur, potentially causing ventricular arrhythmias. Patients with risk factors require ECG monitoring. Correct hypokalemia and hypomagnesemia and avoid concurrent QT-prolonging drugs where possible.
• Drug Interactions:  Because it is metabolized by CYP3A4, it interacts with drugs affecting this enzyme. Strong inhibitors may require dose reduction; strong inducers should be avoided. Consult the detailed interaction list.
• Pregnancy and Breastfeeding: It may cause embryotoxicity and teratogenicity and is absolutely contraindicated in pregnancy. Women of reproductive age should use effective contraception during treatment and for at least 2 weeks afterward. It is also contraindicated during breastfeeding.
• Before Surgery: Pralsetinib may affect wound healing and vascular integrity. It is recommended to stop treatment several days before elective surgery and not resume it until healing is complete.

Adverse Reactions

• Constipation 45%
• Fatigue 40%
• Hypertension 30%
• Increased AST (liver enzyme) 28%
• Increased ALT (liver enzyme) 23%
• Anemia 23%
• Neutropenia 22%
• Cough 22%
• Leukopenia 20%
• Musculoskeletal pain 19%
• Diarrhea 19%
• Hyponatremia 17%
• Nausea 16%
• Headache 15%
• Thrombocytopenia 14%
• Dysphagia (difficulty swallowing) 13%
• Peripheral edema 12%
• QT prolongation 10%
• Vomiting 9%
• Fever (pyrexia) 8%
• Skin rash 8%
• Abdominal pain 7%
• Dyspnea (shortness of breath) 6%
• Dry mouth 5%